We have developed a mathematical method based on the law of energy conservation that uses the measured time course of body weight and food intake to estimate the underlying continuous-time dynamics of energy expenditure and fat oxidation. We applied this methodology to data from our recent study of persistent obesity in male C57BL/6 mice consuming various ad libitum diets during both weight gain and loss. We calculated the first continuous-time estimates of energy expenditure and fat oxidation underlying the observed body composition changes and showed that transient energy and fat imbalances in the first several days following a diet switch account for a significant fraction of the total body weight change. We also discovered a time-invariant curve relating body fat and lean masses in male C57BL/6 mice and the shape of this curve (which is qualitatively different from that of humans) determined how diet, fuel selection, and body composition are interrelated. We hypothesize that genetic manipulations can alter the curves shape and that our methodology can be used to help characterize metabolic phenotypes in various mouse models of obesity and obesity resistance. We are also developing an explicit model of mouse energy expenditure to complement our current model of body composition change and fuel selection. This will allow prediction of body weight as an output variable given only food intake as an input. We also plan to develop a more mechanistic computational model of mouse macronutrient metabolism and body composition regulation (similar to the human computational model) to better understand the physiological mechanisms of metabolic fuel selection and body composition regulation in various mouse models.